1. Field of the Invention
The present invention relates to therapeutic methods, screening methods, and composition comprising a cathepsin K complex exhibiting specific collagenolytic activity.
2. Related Art
Cathepsin K is a cysteine protease of the papain family that is highly expressed in bone and cartilage-degrading cells such as osteoclasts, giant multinucleated cells and synovial fibroblasts. It is estimated that cathepsin K constitutes approximately 98% of all cysteine protease activities expressed in osteoclasts, and thus may be primarily responsible for most of the proteolytic activity in bone resorption.
Cathepsin K has a unique collagenolytic activity that allows the efficient degradation of native collagen fibers. Since type I collagen constitutes more than 90% of the organic bone matrix and type II collagen is the major protein in cartilage, collagen degradation is thought to be the major biologically-relevant activity of cathepsin K.
Cathepsin K has been identified as a novel pharmaceutical target for the design of anti-resorptive drugs. The main indications for the use of cathepsin inhibitors are osteoporosis, Paget's disease, rheumatoid arthritis, and possibly osteoarthritis. The common feature of these diseases is the excessive and irreversible degradation of extracellular bone and cartilage matrix.
Cathepsin K is expressed in a variety of additional cell types such as macrophages, and various epithelial cells with potential functions in antigen processing, thyroglobulin processing and other functions yet to be determined. Thus, active-site directed inhibitors against cathepsin K which result in inhibition of excessive extracellular matrix degradation, will also inhibit many other biologically important cathepsin K activities. Thus, inhibition or disruption of non-deleterious cathepsin K activities may result in undesirable and deleterious effects.
It would be useful to specifically inhibit a single cathepsin K activity, for example, collagen degradation, without inhibiting other biologically-relevant activity.